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Hum Mol Genet. 2015 Nov 1;24(21):6229-39. doi: 10.1093/hmg/ddv341. Epub 2015 Aug 26.

Intravitreal delivery of a novel AAV vector targets ON bipolar cells and restores visual function in a mouse model of complete congenital stationary night blindness.

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Department of Ophthalmology and.
Department of Ophthalmology and Visual Sciences.
Department of Anatomical Sciences and Neurobiology and.
Centre for Molecular Medicine and Therapeutics at the Child and Family Research Institute, University of British Columbia, Vancouver, BC, Canada V5Z 4H4, Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada V6T 1Z3.
Department of Biochemistry and Molecular Biology, University of Louisville, Louisville, KY 40202, USA.
Department of Ophthalmology and Visual Sciences, Department of Anatomical Sciences and Neurobiology and.
Louis Stokes Cleveland VA Medical Center, Cleveland, OH 44106, USA, Cole Eye Institute, Cleveland Clinic, Cleveland, OH 44195, USA and Department of Ophthalmology, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH 44195, USA.
Department of Ophthalmology and, Department of Molecular Genetics and Microbiology, University of Florida College of Medicine, Gainesville, FL 32610, USA,


Adeno-associated virus (AAV) effectively targets therapeutic genes to photoreceptors, pigment epithelia, Müller glia and ganglion cells of the retina. To date, no one has shown the ability to correct, with gene replacement, an inherent defect in bipolar cells (BCs), the excitatory interneurons of the retina. Targeting BCs with gene replacement has been difficult primarily due to the relative inaccessibility of BCs to standard AAV vectors. This approach would be useful for restoration of vision in patients with complete congenital stationary night blindness (CSNB1), where signaling through the ON BCs is eliminated due to mutations in their G-protein-coupled cascade genes. For example, the majority of CSNB1 patients carry a mutation in nyctalopin (NYX), which encodes a protein essential for proper localization of the TRPM1 cation channel required for ON BC light-evoked depolarization. As a group, CSNB1 patients have a normal electroretinogram (ERG) a-wave, indicative of photoreceptor function, but lack a b-wave due to defects in ON BC signaling. Despite retinal dysfunction, the retinas of CSNB1 patients do not degenerate. The Nyx(nob) mouse model of CSNB1 faithfully mimics this phenotype. Here, we show that intravitreally injected, rationally designed AAV2(quadY-F+T-V) containing a novel 'Ple155' promoter drives either GFP or YFP_Nyx in postnatal Nyx(nob) mice. In treated Nyx(nob) retina, robust and targeted Nyx transgene expression in ON BCs partially restored the ERG b-wave and, at the cellular level, signaling in ON BCs. Our results support the potential for gene delivery to BCs and gene replacement therapy in human CSNB1.

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